Chronic alcohol abuse causes immune deficiency and an increase in manifestations of autoimmunity. Significant increases in pneumonia and other infectious diseases in alcoholics result in major morbidity and medical expense compared with non-abusing populations. Our work is part of a long-term strategy to define the alterations leading to the loss of normal immunologic function in the alcoholic. Others and we have shown previously that chronic alcoholics have activated T cells, activated monocytes, and selective lymphocyte subset loss. In experimental rodent models of alcohol administration, changes in splenic lymphocyte populations and function have been found, and a reduction in Th1 cytokine production such as IFN monocyte has been demonstrated in mice after short-term alcohol diets. In contrast, we have recently placed mice on longer-term alcohol, and agree that initial suppression of IFN monocyte does occur, but after 6 weeks, increasing activation is seen which is similar to the activation demonstrated in human alcoholics. Activation parameters in the chronic alcoholic mice include 1) increased CD4+ responsiveness to stimulation through the T cell receptor (TCR), with increased upregulation of CD40 ligand and other activation markers; 2) increased rapid production of IFN monocyte by both CD4+ and CD8+ T cells; 3) increased monocyte numbers, and up-regulation of the molecules involved in second signal transmission to T cells, CD80 and CD86. These findings in mice suggest that the innate immune system (especially monocytes) is first activated by chronic alcohol abuse, followed by activation of T cells by the activated monocytes. We will test this and other mechanisms of T cell activation and loss in several ways. We will: 1) evaluate the stimulatory effect of the monocytes of chronic alcoholic mice on the activation of their T cells; 2) determine whether there is a second signal requirement acting through CD28 for T cell activation in the alcoholic mice; 3) mimic bacterial translocation by exposure to defined substitutes for bacterial DNA, and determine whether this products alterations of the T cell balance (antigen-specific T cell loss, and Th1/Th2 skewing) in the alcoholic mice; and 4) continue the work in human alcoholics by evaluation in restimulation assays, of Th1/Th2 skewing, and the effects of their activated monocytes on T cell proliferative activity after stimulation through the TCR.